Tendons are dense, load-bearing tissues that transmit muscle forces to the skeleton. Upon traumatic injury or degeneration, load-bearing function is frequently compromised due to poor intrinsic healing that is dominated by fibrotic scar formation. Despite tremendous interest, the biology of tendon healing remains poorly defined and many of the cell and molecular factors that mediate these events have not been identified. One major signaling pathway with high therapeutic potential for tendon is TGF?, which has been implicated in multiple aspects of tendon cell biology including development, regeneration, and fibrosis. Despite the importance of TGF? signaling, the mechanisms by which TGF? may drive these divergent processes remain unknown, which has limited effective therapeutic application. Therefore, the goal of our proposal is to distinguish the tenogenic vs. fibrotic functions of TGF? signaling in the context of injury using a novel model of neonatal regenerative healing and a model of adult fibrotic healing. Using inducible mouse technology which enables cell-specific targeting and temporal control of gene recombination, we will determine the role of TGF? (Aim 1) and downstream Smad (Aim 2) signaling in the specific cell populations that drive healing. Aim 3 will use a tissue engineering platform to determine whether limitations in adult tendon healing are due to poor intrinsic tenogenic capacity and identify potential Non-Smad mediators of tenogenesis. Successful completion of this project will uncover the tenogenic vs. fibrotic requirements for TGF? and Smad signaling, which will ultimately enable the development of targeted cell therapies modulating TGF? signaling to enhance tendon differentiation while attenuating fibrosis.